Nanoliposomal irinotecan (MM-398, nal-IRI) population pharmacokinetics (PK) and its association with efficacy and safety in patients with solid tumors based on the phase 3 study NAPOLI-1 and five phase 1 and 2 studies

Results: In
NAPOLI-1, compared to patients treated with 120mg/m2 q3
weeks, nal-IRI 80mg/m2 q2 weeks had similar
Cavg, but 1.5-fold lower Cmax for both IRI
and SN-38. In patients treated with nal-IRI+5FU/LV, higher SN-38
Cavg was associated with improved OS, PFS, and ORR. In a
pooled analysis of 353 patients from 6 studies, SN-38
Cmax was associated with grade 3+ neutropenia and IRI
Cmax was associated with grade 3+ diarrhea. Based on PK
analysis of 353 patients, significant covariates to IRI were
ethnicity and BSA and covariates to SN-38 were baseline bilirubin
and BSA. No other covariates, including UGT1A1*28, were
significant. When nal-IRI exposures and incidence rates of AEs were
predicted from a dose of 80mg/m2, Asians (43%) had a 0.5
x lower IRI Cmax than Caucasians (5% lower predicted
grade 3+ diarrhea), but a 1.5 x higher SN-38 Cmax than
Caucasians (7% higher predicted grade 3+ neutropenia). Patients
with bilirubin 1.0–2.0mg/dL (n=20) had a 1.4 x higher SN-38
Cmax vs patients with bilirubin <1.0mg/dL.

Conclusions:
Lower-dose nal-IRI given more frequently was predicted to have
similar Cavg and lower Cmax. IRI
Cmax was associated with diarrhea and SN-38
Cmax with neutropenia. Asians had lower IRI, but higher
SN-38. Increasing baseline bilirubin was associated with higher
SN-38 levels. Association between SN-38 and efficacy endpoints is
consistent with the preclinical observation that nal-IRI increased
prolonged intratumoral delivery.

Nanoliposomal irinotecan (MM-398, nal-IRI) population pharmacokinetics (PK) and its association with efficacy and safety in patients with solid tumors based on the phase 3 study NAPOLI-1 and five phase 1 and 2 studies